rs78564552

Variant names:

• chr3-3175249-C-T
• rs78564552
• NM_016302.4:c.88G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_016302.4(CRBN):​c.88G>A​(p.Glu30Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00344 in 1,610,774 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (13 hom.)
• Consequence: CRBN NM_016302.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 7.16
• Publications: 8 publications found

Genes affected

CRBN (HGNC:30185): (cereblon) This gene encodes a protein related to the Lon protease protein family. In rodents and other mammals this gene product is found in the cytoplasm localized with a calcium channel membrane protein, and is thought to play a role in brain development. Mutations in this gene are associated with autosomal recessive nonsyndromic cognitive disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

CRBN Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual disability, autosomal recessive 2

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070037544).
• BP6: Variant 3-3175249-C-T is Benign according to our data. Variant chr3-3175249-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210764.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00261 (396/151976) while in subpopulation NFE AF = 0.00471 (320/67950). AF 95% confidence interval is 0.00428. There are 0 homozygotes in GnomAd4. There are 181 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016302.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRBN	NM_016302.4	MANE Select	c.88G>A	p.Glu30Lys	missense	Exon 2 of 11	NP_057386.2
	CRBN	NM_001173482.1		c.85G>A	p.Glu29Lys	missense	Exon 2 of 11	NP_001166953.1	Q96SW2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRBN	ENST00000231948.9	TSL:1 MANE Select	c.88G>A	p.Glu30Lys	missense	Exon 2 of 11	ENSP00000231948.4	Q96SW2-1
	CRBN	ENST00000432408.6	TSL:1	c.85G>A	p.Glu29Lys	missense	Exon 2 of 11	ENSP00000412499.2	Q96SW2-2
	CRBN	ENST00000450014.1	TSL:1	c.73G>A	p.Glu25Lys	missense	Exon 2 of 5	ENSP00000392073.1	J3QT51

Frequencies

GnomAD3 genomes AF: 0.00261 AC: 396 AN: 151860 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000508

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00190

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00471

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00260 AC: 653 AN: 251208 AF XY: 0.00275

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.00483

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00352 AC: 5139 AN: 1458798 Hom.: 13 Cov.: 29 AF XY: 0.00352 AC XY: 2556 AN XY: 725986

African (AFR) AF: 0.000479 AC: 16 AN: 33422

American (AMR) AF: 0.000604 AC: 27 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.000534 AC: 46 AN: 86162

European-Finnish (FIN) AF: 0.00178 AC: 95 AN: 53274

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.00427 AC: 4740 AN: 1109396

Other (OTH) AF: 0.00302 AC: 182 AN: 60292

GnomAD4 genome AF: 0.00261 AC: 396 AN: 151976 Hom.: 0 Cov.: 33 AF XY: 0.00244 AC XY: 181 AN XY: 74280

African (AFR) AF: 0.000506 AC: 21 AN: 41480

American (AMR) AF: 0.00164 AC: 25 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00190 AC: 20 AN: 10508

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00471 AC: 320 AN: 67950

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00396 Hom.: 2

Bravo AF: 0.00237

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00279 AC: 339

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00551

EpiControl AF: 0.00391

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.044	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.082
Sift	Uncertain	0.029	D
Sift4G	Benign	0.082	T
Polyphen		0.18	B
Vest4		0.21
MVP		0.79
MPC		0.11
ClinPred		0.050	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.40
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs78564552; hg19: chr3-3216933;